Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform

Our plain-English summary of Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform, by S.D. Forsythe, R.A. Erali, N. Edenhoffer, et al (Scientific Reports, 2023).

The study

• Authors: S.D. Forsythe, R.A. Erali, N. Edenhoffer, W. Meeker, N. Wajih, C.R. Schaaf, P. Laney, C.D. Vanezuela, W. Li, E.A. Levine, S. Soker, K.I. Votanopoulos
• Journal: Scientific Reports
• Published: 2023;13(1):11640
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

In plain English

In this laboratory study, researchers at Wake Forest grew small three-dimensional tumor models (organoids) from 17 tumors removed from 7 peritoneal mesothelioma patients during surgery between October 2020 and November 2022. They treated the organoids with two drugs used in heated chemotherapy given inside the abdomen (HIPEC), cisplatin and mitomycin C (MMC), at 42 °C and at 37 °C (body temperature), then measured how many cells survived. Heat significantly lowered cell survival with cisplatin (38.3% versus 62.6% viable). With MMC the drop (50.6% versus 73.3%) was not statistically significant. Heated cisplatin met the authors' definition of effective in 12 of 16 tumors, and heated MMC in 7 of 16. Pooled across tumors, the difference between heated cisplatin and heated MMC was not statistically significant. Tumor by tumor, cisplatin worked significantly better in 5 of 16 and MMC in 2 of 16. Responses varied between patients and between sites within one patient. The authors concluded that cisplatin was superior to MMC, and noted their modest cohort as a limitation. The study did not address asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (ex vivo) study of patient-derived tumor organoids made from surgical tumor specimens and treated under simulated HIPEC conditions
• Who was studied: 17 tumors from 7 peritoneal mesothelioma patients undergoing cytoreductive surgery with HIPEC at Wake Forest, October 2020 to November 2022. One organoid group was not viable enough for testing, leaving 16. Six patients had epithelioid or biphasic tumors and one had well-differentiated papillary tumor with invasive foci.
• Exposure: Not an asbestos exposure study. Organoids were treated with mitomycin C (40 mg/3 L for 120 minutes) or cisplatin (125 mg/m2 for 90 minutes), each at 37 °C and 42 °C, compared with untreated controls
• Main results:
  • Pooled across organoids, heat significantly increased cisplatin's cell-killing effect (38.3% viability at 42 °C vs 62.6% at 37 °C, p = 0.02). For MMC the difference was a trend that was not statistically significant (50.6% at 42 °C vs 73.3% at 37 °C, p = 0.10).
  • Heated cisplatin met the efficacy definition in 12/16 (75%) tumors, with average viability 38% (range 5 to 68%). Heated MMC met it in 7/16 (43.8%) tumors, with average viability 51% (range 17 to 92.3%).
  • In the pooled comparison of heated cisplatin with heated MMC, the difference was not statistically significant (38.3% vs 50.6%, p = 0.10).
  • At the level of individual organoid sets, heated cisplatin was significantly more effective in 5/16 (31.3%) and heated MMC in 2/16 (12.5%).
  • In one patient with biphasic tumor (Patient 6), organoids from a colon implant were sensitive to both drugs at both temperatures. Organoids from an ovary implant were resistant to MMC and sensitive only to heated cisplatin.
• The authors' conclusion: The authors concluded that cisplatin showed superiority and increased efficacy under heated conditions compared with mitomycin C in peritoneal mesothelioma organoids. They also concluded that organoids can serve as a platform to test treatment sensitivity.
• Limitations the authors state:
  • The rarity of peritoneal mesothelioma and its division into subtypes resulted in a modest study cohort
  • Correlating organoid results with patients' clinical outcomes is difficult because disease varies between lesions
  • Sequencing data were not obtained

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Peritoneal Mesothelioma, HIPEC, Prognosis, Mesothelioma, Cytoreductive Surgery, Mitomycin C.

Related studies

• Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for malignant peritoneal mesothelioma: mitomycin versus cisplatin — A.U. Blackham, P. Shen, et al. (2010)
• Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in pediatric patients with peritoneal mesothelioma: a single institution experience and long term follow up — P. Malekzadeh, M. Good, et al. (2021)
• Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence — E.A. Makris, J.K. Ives, et al. (2026)
• Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury — L.F. Liesenfeld, E. Quiring, et al. (2023)
• Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study — B. Malgras, E. Gayat, et al. (2018)
• Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent peritoneal metastases — T.C. Chua, L.E. Quinn, et al. (2013)

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